Ionis Pharmaceuticals Inc (IONS) September 2026 Conference Transcript

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Goltz, one of the biotech analysts, and it's my pleasure to introduce Brett Moynia, CEO of Ionis Pharmaceuticals. Just a reminder, the format for today is the Fireside Chat, but before we start, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com backslash research disclosures. disclosures, and if you have any questions, please reach out to your Morgan Stanley sales representative. And with that, I'll hand it over to Brett. Thanks for joining us, and maybe you can start with a couple introductory comments before we hop into Q&A.

Yeah, thanks, Mike. Good morning, everybody. It's great to be here, Mike. Thanks for the invite. So as expected, and not surprising with a pipeline as deep and rich as ours, We were expecting a highly eventful year for Ionis, and that's exactly where we are with a lot more to come in the remaining months of the year. You know, we're on track this year to push three breakthrough medicines across the finish line through the FDA, three drug approvals. We already have two. Severe hypertriglyceridemia, breakthrough medicine, Tringolza, was approved a few days early in June. And just last week, we had the approval of our first Holyone Neurology Medicine, Zambastro, for Alexander disease, the first disease-modifying treatment ever approved by the FDA. And we're expecting a third FDA approval in October with our partner GSK for chronic HPV, a real breakthrough that's actually producing unprecedented functional cures in this patient population. we've also had expanding our phase 3 pipeline we initiated we completed enrollment in our phase 3 angelman's trial which is on track for data in the second half of this year and we're pleased to see new phase 3 starts from our partners Sal and Erson the first follow on to Spinraza for SMA that is on track for to produce a medicine with even deeper efficacy than Spinraza based on biomarker data with once-per-year administration. And then Sapa Blurson started phase three development with our partner Ono this year with a profile that has the potential to be a best-in-class for polycythemia vera. Mid-stage pipeline continues to produce as well. We are thrilled with the first-ever proof-of-concept for our tau program with Biogen, Duranderson, which showed unprecedented improvements in cognition and other functional benefits as well. And then our follow-on to Tringol's, a proof of concept as a once-a-year or twice-a-year administration as a follow-on to Tringol's, that ION 775 in severe hypertriglyceridemia, which is in Phase II development. With a pipeline as deep and with so many events happening, there's always disappointment. We are disappointed with the negative outcome of the CardioTransform study for eplontersin and TTR cardiomyopathy. Despite the fact that we had remarkable reductions in TTR that were as good as anything that's out there today, approximately 80% reduction with good safety and tolerability, didn't hit the composite primary endpoint. That was a key focus at ESC a couple of weeks ago where the conclusions were clear that the reason why we didn't hit the primary endpoint was because there was no added benefit on top of a stabilizer. However, the monotherapy group, that is patients that weren't on stabilizer at baseline, has a ratio that's as good as anything that's out there in TTR cardiomyopathy, a hazard ratio of approximately 30% reduction. And we're working on potential next steps there. And then last week we were also disappointed with the outcome of the Pellic-Larsen phase 3 trial and LP little a cardiomyopathy. and we're looking forward to our partner Novartis presenting the full data set there. But on top of those disappointments, we have a really, really strong pipeline and we're really proud of all the successes we've had and the launches that are in progress, which are going quite well.

Great. Thanks for that introduction. And a lot going on and a lot to cover here. So maybe we'll start just with the SHTG launch. I think you're two months in now, still very early here, but maybe just talk about what you're seeing there in terms of trends and how that's all progressing.

We're pleased to have delivered the real breakthrough for severe hypertriglyceridemia with an incredibly strong, positive, clean label. Unprecedented reductions in acute pancreatitis. This is the outcome that patients are most fearful of, that physicians are most fearful of, a potentially fatal acute pancreatitis attack. There has been no meaningful treatments for severe hypertriglyceridemia before tringolza emerged and was approved by the FDA. As a reminder to everybody, this is a label expansion. Our first indication was familial chylomicronemia syndrome, FCS, a rare population of about 3,000 people in the United States. That launch was going exceptionally well, right up to the label expansion, right up to the approval for severe hypertriglyceridemia. And then we expanded the label, adjusted the price from a rare disease price to a price that's more suitable for a highly prevalent disease, prevalence of more than 3 million people in the United States. So this is positioned to be a blockbuster. And we're on track to achieve our goal of $3 billion-plus peak product sales in the United States. The launch is going well. We're liking what we're seeing on all aspects of the launch to date, the metrics that we're assessing. First of all, we're thrilled with the excitement by the HCP community. I'm sure you've done your research. You've talked to your docs. They're all saying how excited they are about Tringolza and their enthusiasm to want to treat and write scripts and get their patients on this drug, particularly those patients that are at high risk for acute pancreatitis. The launch is going well. We're excited about the enthusiasm. We're excited about the scripts that are coming in. July and August were very good months, and we're excited about what we're seeing from the payer community, the coverage that we're getting. for Tringolza, you know, although, of course, at this stage of the launch, most coverage is going through a medical exception process with prior authorizations, but we are getting policies in place, and based on those policies, as well as all the other conversations we're having with payers, we're getting coverage to label, right, not just the high-risk patient population, but the label, that is anyone that has triglycerides above 500. We expected the patients that were going to be prioritized in this study would be those high-risk patients by physicians, endocrinologists, cardiologists, lipid specialists, and that's what we're seeing. These are the patients that have triglycerides through the roof, above 880 milligrams per deciliter, at high risk for acute pancreatitis attack, with debilitating effects on the pancreas, of course, long-term, and those that haven't had a history of acute pancreatitis, you know, around 700, 800, 900,000 patients that are high risk. Those are the ones that we're seeing the scripts written for first, not surprisingly. I could also tell you, though, we are seeing some scripts coming in that are in the non-high-risk category, patients that are in the 500 to 800 range without a history of acute pancreatitis. So, you know, that's getting out there, too. but the priority for us and the priority with HCPs is the high-risk patient population. I could also say that we're excited or we're really pleased how well the dosing is resonating with the HCP community. You know, we are the only medicine that offers dosing flexibility of 50 milligrams or 80 milligrams per month. So, administered using a simple auto-injector. That dosing flexibility, as I said, has resonated really well, and we're seeing Scripps come in with the 50-milligram dose, and physicians are looking at the response to 50 milligrams and seeing, you know, if their patients are at goal, that is below 500 milligrams per deciliter, they're fine. We're also seeing Scripps come in at 80 milligrams right out of the gate. Remember, the 80-milligram dose is what's approved in FCS. We have a lot of docs that are managing FCS patients and are really pleased with the performance of tringolza in FCS, and they're saying, why start at 50 in my SHTG patients? Just roll it right through and get those patients to the max dose. We're also pleased how the response by the community, the physicians and the patients, because we require no monitoring, in the study. It's a simple administration, really no significant step edits. You know, your patients will need to be on a triglyceride drug, like a fibrate or a fish oil or something like that before going out to tringolza. But all these high-risk patients are already on these drugs, right? They're still not at goal, so it's not really a step edit. It's just, you know, getting those patients identified and bringing them onto tringolza. So, hey, this is a, new category. We're developing a new category. We're going to build this market. It's going to take a little bit of time, but we're pleased with the way the enthusiasm for the drug, and we're pleased with everything we're seeing with the launch today. We're looking forward to providing a more detailed update at our Q3 earnings in a few weeks.

Great. Sounds like things are on track there, but maybe you could talk about keys to driving the continued success of the launch, kind of near-term and then longer-term?

The keys are, you know, disease awareness and drug awareness, making the physicians aware of the remarkable profile that Tringolza offers, efficacy, convenience, tolerability, and the dosing flexibility that I highlighted with no monitoring in the study or for the drug. So that has resonated really well. Launching off of FCS. All the docs that manage FCS patients also manage SHTG patients, and that experience has been so positive that we've really been able to build off of that leverage. Focusing in addition to physician HCP awareness and education is patient awareness. Know your triglycerides. Get them measured. Omnichannel, direct-to-consumer dissemination of information, the risks of high triglycerides. We're going from the top, pushing down. We're going from the bottom, pushing up. Patients, and as I mentioned already, focusing on payer coverage and ensuring that we have a strong HCP and patient support program. We are emphasizing and prioritizing making the scripts that docs want to write, bringing that all the way through the process in the most seamless, easiest way possible. It's really important to us, and our patient support program is a top priority, and it served us very well in FCS and off to a good start in SHTG, and we think it will serve us very well in the SHTG launch today. I want to emphasize we remain very confident in our peak product sales of $3 billion plus in the U.S. It's going to take a little time to get there, but we're confident we're going to get there, and we're really looking forward to a big, big 2027.

Great. I also wanted to just ask your view on sort of these third-party scripts. You know, a lot of people are taking a look at them. What's your sort of sense there?

Yeah, we don't believe that the Symfony scripts and QVIA are a good measuring stick for what's happening in the launch. Like most companies do, we block our data, and we have several specialty pharmacies now that we're utilizing, not just one that we use for FCS. So you really can't compare the FCS data with the SHTG data and extrapolate. It's dangerous. It's unreliable. We'd really caution against that. Instead, I'd point you to the color we're looking forward to providing at our end of Q3 earnings and then next year at our end of our full-year earnings, I think, in February of next year. So we're very cautious of that. We don't believe the data is reliable.

Yep, understood. Can you maybe talk about the reaction to the safety profile of Tringolza that you're seeing? And I guess, you know, liver fat has been one area. You know, is that an issue, not an issue? What are you hearing?

We're hearing everything is positive about the safety profile for tringolza. You know, again, I said it twice now. There's no monitoring for anything, LFTs. We have a very clean profile. Liver enzymes are clean. Everything is clean. We're really pleased with the adherence. Patients are getting on to drug. They're seeing their triglycerides plummet. get to normal, and in most cases, in many cases, and the adherence is excellent. The HCPs are enthused about it. Liver fat is small. It's on target, and it wanes with continued treatment while triglycerides are being maintained and highly controlled, and AP is being, it's an on-target effect. We know how APOC3 works by inhibiting APOC3. We're substantially and very rapidly lowering triglycerides in these patients. And one of the pathways that we're lowering triglycerides is through the liver and the clearance. We see a small increase in liver fat. It's not even statistically significant at 50. In many patients, most patients get the goal at 50 milligrams. In the 80, we saw a slight increase that was statistically significant at the end of the Phase III study. But then with continued dosing, it wanes and comes back to baseline. The liver is adapting to this. We have a competitor program. There's a competitor that is following us. They're behind us by almost about a year or so. We're expected to come in on SHTG and get approval. Although they didn't evaluate nearly the number of patients that we did, we evaluated because we really wanted to flesh out the full profile, like what do we need to know for Tringolza? We evaluated 250 patients by MRI. They evaluated a few dozen. But even with that few dozen at ESC, it was clear that you saw a numerically increase in hepatic fat. So it's an on-target effect that's completely manageable. Most importantly, by the HCP community, it's a non-issue. It really never was an issue. And now the fact that they see it come back down to baseline with continued treatment, it's even less of an issue.

Yep, makes sense. You mentioned the competitor. I don't know if you can maybe talk a little bit more about key points of differentiation and, you know, since they might get to the market next year, kind of what impact could that have on your sort of launch?

Yeah, so we're first to market by about a year, like I said, and we actually believe that having two players, like a duopoly, is very few in this massive market opportunity. More than 3 million people that are inadequately or not adequately being addressed with current treatments. We actually think that that's going to provide an opportunity to grow the market, share a voice, better disease awareness by having two players actually expand the market with all of that. But we're going to take advantage of our first-to-market strategy. Our strategy is to build those contracts with payers, build first-mover advantage to get to those high-risk patients first. bring them on to Tringolza, we're confident once they come on to Tringolza they're going to be really pleased with the experience that they have, the ACPs as well as the patients. As far as differentiation, the two drugs look very similar. Efficacy, very, very highly efficacious. AP reductions, you know, we think that we like our data a lot. We are looking forward to more details of our competitors' data. We saw what was presented at ESC, but we really do want to see the publication. It's really important to really get into the details and that kind of thing. So it's hard to say, but overall there's no surprises. The two drugs should work similarly. We're getting identical reductions of target, A plus C3. They should translate to similar efficacy. And we welcome two players in this really large market opportunity.

Yeah, makes sense. Also, in your prepared remarks, you mentioned 775, your sort of next-gen program. Maybe talk a little bit more about that in terms of the data you've seen and timelines and path forward.

Yeah. So, you know, when I became the CEO, I guess this is my seventh year now, Not only did I commit to fully integrating the company and building our wholly owned pipeline, delivering our medicines, I also committed to expanding and diversifying our technology. ASO, the newest chemistries, like I mentioned, salinersin, that's an ionist chemistry that is supporting once-per-year dosing for SMA. We have more coming. Our Dravet's program is using that same chemistry. We've expanded into siRNA. SiRNA is more durable in the liver. We know that. but we've been able to take it to the next level with Ionis experience, the capabilities, chemistries, and so on. And we've applied that to a follow-on to Tringolzin. Recognizing that a once-per-year dosing or maybe twice-a-year dosing at a minimum, we can easily achieve that, but maybe push it to once-per-year dosing, could really matter from a convenience standpoint for HCPs and patients.

And we think our phase one data supports that.

We tested 775, an IONIS discovered using our chemistry, SI, that showed incredibly durable reductions of target, A plus C3, triglycerides, all good safety and tolerability, dose dependent. And we've already, and that was a normal volunteer study in patients with mildly elevated triglycerides. That was presented at ASC, published now as well. Well, kind of old news, though. We have already launched into Phase II development in SHTG, and we're enrolling quickly. Our goal is to protect Tringolza. It's a blockbuster. We're the ones that innovated. We're the ones that came up with this program. We're the ones that came up with this target for this disease, and we want to make sure that we have next waves of approaches for this market opportunity. It's an open-label study purposely so that we can look at the data daily and look at target reduction, safety, and triglyceride reduction so that we can select the dose and dose interval and get into phase 3 development as rapidly as possible, potentially next year.

Great. What's your thought on the strategy there? Is it a replacement for tringolza? Is it for a different patient population? What's the early thinking?

To be determined. We'll see what the profile looks like. And we have to do our, you know, our team is going to be doing the market research. Could it be complementary to Tringolza? Or would it be the next, you know, best-in-class molecule for SHTG overall? And it could take everything over. We'll see about that. I suspect it will be complementary to Tringolza. and we may be able to position it in different ways so that it offers something that Tringolza doesn't offer and Tringolza could offer something that 775 doesn't offer, to be determined. We need to get into Phase 3 and move it quickly. We're working on the Phase 3 design now. I expect it won't look that different than our Phase 3 program for Tringolza. Just FDA has requirements. But we think we'll be able to trim those timelines down and move faster, even faster than what we did for the phase three program for tringolism.

Yep, understood. You mentioned in your starting comments here about cardio transform and data was a little bit disappointing, so maybe you can expand on that and what you think happened there and then also what's the latest thinking on next steps. Is that evolving at all or where is that currently?

Yeah. As I mentioned in my opening comments, we were disappointed that we didn't hit the positive. We didn't have a positive outcome against the primary endpoint in the CardioTransform study, Eplon-Tursin for TTR cardiomyopathy. We had 80% reductions in TTR, which was pretty much the best you can do in this population, at least for current drugs that are out there that are addressing this disease. good safety, good tolerability, but we didn't hit the primary endpoint. You know, we all had hoped that, we all expected that the stabilizer that was primarily used in this study, and we had more than 56% of patients on tefaminis at baseline. Tefaminis is the standard of care. That was the only way to really run the study today. And as tefaminis is standard of care in the U.S., and as the markets grew outside the U.S., We saw lots of drop-ins, too. But the belief was that to famine, there was a lot of room for improvement, right, based on studies that were done 10 years ago, the ATTRACT study. But those patients were very sick, and patients are being diagnosed much earlier in their disease today, and the faminists did better than what most people had expected because patients were being treated earlier in their disease. That was our control group. That would have been okay had the combination of silencer plus a stabilizer showed added benefit compared to the control, but it didn't. We didn't see any added benefit of combination. That was the conclusion of an independent academic group's meta-analysis at ESC last year. There's no evidence that the combination from any study shows added benefit, nothing deleterious, but nothing beneficial. That was the Achilles heel in the study. that's the study that needed to be done this is the standard of care and we needed to see if we can improve efficacy retrospect maybe it wasn't surprising we're targeting the same pathway stabilizer stabilizing TTR we're blocking the production of the TTR so maybe we've maxed out on efficacy silencers work great on their own stabilizers appear to work very well as well on their own And we think ultimately it will come down to patient and physician preference, which ones they choose, but we don't think there's a path forward for combination for silencers and stabilizers. With that said, in the group that wasn't on stabilizers at baseline, the efficacy was remarkable. We saw nearly a 30% relative risk reduction in the patients that we call the monotherapy group that weren't on stabilizers at baseline. There was a lot of drop-ins, but still they weren't on stabilizers at baseline, And that was comparable to the other silencer that was approved for TTR cardiomyopathy. So the monotherapy data looks great. Our partner and us, AstraZeneca and we, are weighing next steps. And you'll probably have more clarity of that by the end of this year on whether or not we will pursue the monotherapy indication or not. So just stay tuned for that.

Okay. Okay. And if we just stick with the pipeline and, you know, I wanted to get your sort of thoughts on the Angelman program, maybe just give us a brief background there. And obviously competitor shared some data and read through.

Yeah, it was very disappointing when we learned about the failed phase three study with the LEAD program, the program that was in advance, you know, utilizing the same mechanism that we're utilizing. This is a mechanism that we created. We were first to publish on it. We're basically targeting using an antisense strategy to upregulate the paternal UVE3A gene to basically replace a loss-of-function disease with the missing protein, UVE3 protein. It's a really elegant mechanism. And they were using the same mechanism. They saw what we published, and they licensed in a drug. They licensed in a drug from an academic group that did some screening and found a molecule. I want to really highlight the fact that it's not routine to find an optimal molecule to do these kinds of things. It takes us years to optimize potency, durability, and minimize off-target effects to reduce toxicity. But they licensed the molecule and, unfortunately, it caused issues on the safety side that caused them to be capped. Their dose was capped. So they couldn't go above 14 milligrams. Our phase three study program ongoing is 80 milligrams. The two drugs are equal potent. So the potencies are the same. So you can imagine that maybe they underdosed. That's what we believe. And in fact, when we did our phase two study called HALOS, we evaluated 20 milligrams quarterly, which is kind of in that range of 14 that they looked at in their Phase III program, 40 milligrams and 80 milligrams quarterly. At 20 milligrams, we kind of saw some hints of activity, but we weren't convinced. When we went to 40 milligrams quarterly, we were convinced that we were seeing clear evidence of benefit. And when we got to 80 milligrams, our Phase III dose, we got a little bit better, but it looked like we were maxing out on efficacy. Unfortunately, we think that they underdosed in this study. It's devastating for the community. We've been ensuring the community that's in such a desperate need for a disease-modifying treatment for this large patient population, the Angelman syndrome population. But we will be the first to test the hypothesis because we believe that we're in the therapeutic range, the doses that are needed, and we believe that our Phase II data HALOS study strongly supports that. I also mentioned that our long-term extension data, we're now 18 months, data cuts 18 months and beyond from the Phase II HALO study, and the efficacy is holding. We continue to be convinced that we're seeing strong evidence of benefit, and it continues to support Phase III development. And we're going to publish that data soon, the long-term extension data for Angelman's. but we think we got the right drug and this is the right mechanism and this will be the first test of this mechanism to address Angelman syndrome great and if we stick with the wholly owned pipeline and Alexander's disease you mentioned that earlier recently approved ahead of schedule maybe talk a little bit about that program and sort of what it means more broadly for your CNS pipeline yeah we're believe that, you know, I think the evidence is clear that we have led the way, we continue to lead the way in developing oligonucleotide therapeutics, ASO, and now siRNA. We're doing a lot of work there, too, for CNS diseases. I mean, it's proven. We have three approved medicines now. You mentioned Zanvastro for Alexander disease. Preceding those were, of course, Spinraza, the first ever treatment for SMA, and then CalSati, the first disease-modifying treatment for a cause of ALS, and now Zanvastro, and we have a rich, wholly owned, and partnered pipeline of CNS drugs following this, and we're expecting quite a number of readouts next year, in addition to the Angelman's Phase III program, our mid-stage neuro program will have several readouts next year, too. We're very proud of having delivered the first-ever disease-modifying treatment for this devastating neurodegenerative disease, Alexander disease. It's caused by the overproduction of a protein called GFAP. We're normalizing GFAP. We're lowering GFAP. We've shown that, and we're having a disease-modifying impact on clinical outcomes in this study. This is a ultra-rare indication. It's estimated to be 300, 400 patients in the United States with Alexander disease. The prevalence is really not well understood. when we unblinded our phase 3 study we saw the efficacy we opened up an expanded access program immediately and that expanded access program has actually enrolled pretty we were surprised how many patients actually enrolled in that expanded access program our focus is to convert our clinical trial patients and our expanded access patients over to commercial as quickly as possible or in the process of doing that. We're launched. And, of course, patient identification. It's a difficult disease to identify. It's a long patient journey. Every day, these patients aren't on a treatment like Zanvastro. They're one day closer to, usually, to death. So patient identification, disease awareness is a big focus for us, and it's going well. Strategically, this is very important for IONIS because we're leaders in CNS diseases. We have a rich, wholly-owned pipeline that's growing in addition to our partner pipeline. And this is strategic because it's our first wholly-owned launch in neurology. And we have so many more neurology drugs, Angelman's we talked about, and then many other programs that are reading out next year that can go to phase three if they're successful. So it's strategically important for the company. And we're very proud of the fact that, you know, we were first, once again, we were first in delivering a breakthrough treatment for a patient population that is in desperate need.

Great. And maybe last few minutes here, I want to focus back on your commercial assets and Don Zara and HAE. You launched it last year, I think, and maybe just talk about, you know, how that launch Seems like you're getting more traction, you know, more recently and things are accelerating Don Zara's going well.

I mean, this is very different than any of the medicines I just talked about, right? This is a highly competitive market in the sense of there are existing prophylactic treatments for HAE that were already on the market when we arrived, when we were approved last August, or one year into the launch, and more have been coming, right, after that. You know, so this is our first test in commercializing our own medicines, not just being first to market, which usually are, have been, but in a competitive space. I'm proud of the team. I really am. I'm also proud of the drug. It has a real differentiating profile compared to other treatments that are out there with respect to not only efficacy, which is as good as anything that's out there today. So, you know, we've achieved that. the tolerability and the convenience of being able to self-administer once a month or every two months using a simple auto-injector in which the drug is stable for six weeks at a time, longer than that, but the label says six weeks. So you could take it with you on vacation and not be worried about having to refrigerate or reconstitute. It's a real easy drug to work with, and that profile, along with the outstanding effort that our team has done to educate HCPs and patients on the opportunity that Donzera offers, lunch is going well. I mean, you know, it's a steady growth. We're having a good year for Donzera, and we expect next year for it to continue to grow.

All right, great. Looks like we're out of time here, so why don't we wrap it up. Brett, thanks so much for your time. We really appreciate it.

Thank you, Mike. It was a pleasure.